Prompt and error-free repair of critical genomic alterations of toxicant exposures is vital to normal survival of living organisms. During the previous project period, we have shown that global genomic repair lends itself to elaborate regulatory control for orchestrating the """"""""comings and goings"""""""" of multiple repair factors. This continuation project will extend the scope of these studies along a similar overall theme. The proposal is based on the premise that in response to genotoxin exposures, several seemingly independent cellular pathways converge to function in tandem for the distinctive recognition and effective excision of DNA lesions. The specific hypotheses addressed are: (i) entire repair edifice is composed from the initial regulated attaching of DNA damage binding protein that impinges on recruiting subsequent core repair factors, (ii) cellular ubiquitin/proteasome apparatus intimately participates in sequential clearance of repair factors that are tightly bound to damage sites, and (iii) the involved repair protein complexes allow bridging between diverse pathways through multi-acting pleiotropic factors.
The specific aims will focus on: (1) establishing the biochemical/molecular basis for selective damage recognition and recruitment of DDB containing E3 Ub-ligase complex to diverse DNA lesions, (2) defining the role of Ub-mediated proteolysis in lesion hand-over during repair processing, (3) delineating the nature and function of DNA damage dependent XPC modifications, (4) establishing the molecular basis for differential role of hHR23A/B in regulation of XPC ubiquitination/degradation and UV-induced p53 response, and (5) understanding the role of 19S proteasomal components and other cellular deubiquitinating enzymes in regulation of XPC stability. The experimental studies will continue to concentrate on genomic modifications induced by a representative physical (UV radiation) and a chemical (anti-BPDE) genotoxic carcinogens and human cell lines representing multiple organ systems, e.g., skin fibroblast, liver hepatocytes, breast and lung epithelium. State-of-the-art biochemical, molecular and cellular methodologies, mostly established in the PI's laboratory, will be applied along with the newer evolving technologies to accomplish these specific objectives. The studies will provide seminal insights into the molecular responses of xenobiotic action and processing of resultant genotoxic damage which has crucial implication in risk assessment of human environmental exposures.
|Ray, Alo; Blevins, Chessica; Wani, Gulzar et al. (2016) ATR- and ATM-Mediated DNA Damage Response Is Dependent on Excision Repair Assembly during G1 but Not in S Phase of Cell Cycle. PLoS One 11:e0159344|
|He, Jinshan; Zhu, Qianzheng; Wani, Gulzar et al. (2016) Valosin-containing Protein (VCP)/p97 Segregase Mediates Proteolytic Processing of Cockayne Syndrome Group B (CSB) in Damaged Chromatin. J Biol Chem 291:7396-408|
|Han, Chunhua; Srivastava, Amit Kumar; Cui, Tiantian et al. (2016) Differential DNA lesion formation and repair in heterochromatin and euchromatin. Carcinogenesis 37:129-38|
|Qian, J; Pentz, K; Zhu, Q et al. (2015) USP7 modulates UV-induced PCNA monoubiquitination by regulating DNA polymerase eta stability. Oncogene 34:4791-6|
|Zhao, Ran; Cui, Tiantian; Han, Chunhua et al. (2015) DDB2 modulates TGF-Î² signal transduction in human ovarian cancer cells by downregulating NEDD4L. Nucleic Acids Res 43:7838-49|
|Zhu, Qianzheng; Sharma, Nidhi; He, Jinshan et al. (2015) USP7 deubiquitinase promotes ubiquitin-dependent DNA damage signaling by stabilizing RNF168. Cell Cycle 14:1413-25|
|Zhu, Qianzheng; Battu, Aruna; Ray, Alo et al. (2015) Damaged DNA-binding protein down-regulates epigenetic mark H3K56Ac through histone deacetylase 1 and 2. Mutat Res 776:16-23|
|Han, Chunhua; Wani, Gulzar; Zhao, Ran et al. (2015) Cdt2-mediated XPG degradation promotes gap-filling DNA synthesis in nucleotide excision repair. Cell Cycle 14:1103-15|
|He, Jinshan; Zhu, Qianzheng; Wani, Gulzar et al. (2014) Ubiquitin-specific protease 7 regulates nucleotide excision repair through deubiquitinating XPC protein and preventing XPC protein from undergoing ultraviolet light-induced and VCP/p97 protein-regulated proteolysis. J Biol Chem 289:27278-89|
|Sharma, Nidhi; Zhu, Qianzheng; Wani, Gulzar et al. (2014) USP3 counteracts RNF168 via deubiquitinating H2A and Ã½Ã½H2AX at lysine 13 and 15. Cell Cycle 13:106-14|
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